Polymorphic forms of nateglinide

ABSTRACT

Provides are crystalline forms of nateglinide, labeled Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y, α, β, γ, δ, ε, σ, θ and Ω, processes for their preparation and processes for preparation of other crystalline forms of nateglinide. Also provided are their pharmaceutical formulations and methods of administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional applicationsSer. Nos. 60/396,904 filed Jul. 18, 2002; 60/413,622, filed Sep. 25,2002; 60/414,199, filed Sep. 26, 2002; 60/423,750, filed Nov. 5, 2002;60/432,093, filed Dec. 10, 2002; 60/432,962, filed Dec. 12, 2002;60/442,109, filed Jan. 23, 2003; 60/449,791, filed Feb. 24, 2003; and60/479,016, filed Jun. 16, 2003, the contents of all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the solid state chemistry ofnateglinide.

BACKGROUND OF THE INVENTION

Nateglinide, known as(−)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-Phenylalanine, has thefollowing structure and characteristics:

Formula C₁₉H₂₇NO₃ Molecular Weight 317.42 Exact Mass 317.199093Composition C 71.89% H 8.57% N 4.41% O 15.12%

Nateglinide is marketed as STARLIX, which is prescribed as oral tabletshaving a dosage of 60 mg and 120 mg for the treatment of type IIdiabetes. STARLIX may be used as monotherapy or in combination withmetaformin to stimulate the pancreas to secrete insulin. According tothe maker of STARLIX, nateglinide is a white powder that is freelysoluble in methanol, ethanol, and chloroform, soluble in ether,sparingly soluble in acetonitrile and octanol, and practically insolublein water.

Nateglinide may be crystallized out of a mixture of water and methanol,and further dried, as disclosed in U.S. Pat. No. 4,816,484. Theprocedure of the '484 patent results in a hydrate labeled by the presentApplicant(s) as Form Z, or in a methanolate lablelled by theApplicant(s) as Form E. Drying of the wet sample results in Form B.

The present invention relates to the solid state physical properties ofnateglinide. These properties may be influenced by controlling theconditions under which nateglinide is obtained in solid Form. Solidstate physical properties include, for example, the flowability of themilled solid. Flowability affects the ease with which the material ishandled during processing into a pharmaceutical product. When particlesof the powdered compound do not flow past each other easily, aformulation specialist must take that fact into account in developing atablet or capsule formulation, which may necessitate the use of glidantssuch as colloidal silicon dioxide, talc, starch or tribasic calciumphosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid may have therapeuticconsequences since it imposes an upper limit on the rate at which anorally-administered active ingredient may reach the patient'sbloodstream. The rate of dissolution is also a consideration informulating syrups, elixirs and other liquid medicaments. The solidstate Form of a compound may also affect its behavior on compaction andits storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic Form of a substance. The polymorphicForm may give rise to thermal behavior different from that of theamorphous material or another polymorphic Form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC) and may be used to distinguish some polymorphic formsfrom others. A particular polymorphic Form may also give rise todistinct spectroscopic properties that may be detectable by powder X-raycrystallography, solid state C NMR spectrometry and infraredspectrometry.

Nateglinide exists in various crystalline forms. U.S. Pat. Nos.5,463,116 and 5,488,150 disclose two crystal forms of nateglinide,designated B-type and H-type, and processes for their preparation. Thesepatents are incorporated herein by reference for their disclosure of theforms. Both forms are characterized by melting point, X-Ray PowderDiffraction (“XRPD”) pattern, IR spectrum in KBr and DSC thermogram.According to these patents, B-type has a melting point of 129-130° C.while H-type has a melting point of 136-142° C. The H-type crystals arecharacterized in these patents by an XRPD pattern with peaks at 8.1,13.1, 19.6 and 19.9±0.2 degrees 2θ, and a strong reflection between 15and 17±0.2 degrees 2θ. The B-type crystal is reported to lack thesepeaks and have a weak reflection between 15 and 17±0.2 degrees 2θ.H-type crystals are reported to have an IR spectrum with characteristicabsorptions at about 1714, 1649, 1542 and 1214 cm⁻¹. These absorptionsare reported to be missing in the spectrum of B-type crystals.

According to U.S. Pat. No. 5,463,116, B-type crystals are unstable andsusceptible to change during grinding as demonstrated by DSC. The DSCthermogram of B-type shows a sharp endotherm at 131.4° C. beforegrinding while that of H-type shows a sharp endotherm at 140.3° C. Aftergrinding, the DSC thermogram of B-type shows a second endotherm at138.2° C., suggesting a solid-solid transformation during grinding.

According to U.S. Pat. No. 5,463,116, the temperature duringcrystallization and filtration determines whether the crystal Form isB-type or H-type. Temperatures above 10° C., more preferably above 15°C., lead to formation of H-type, while those below 10° C. lead toformation of B-type.

Another crystalline form of nateglinide designated Type-S is disclosedin two Chinese articles: ACTA Pharm. Sinica 2001, 36(7), 532-34 andYaowu Fenxi Zazhi, 2001, 21(5), 342-44. Form S is reported to bedistinguisheable from Forms B and H by a melting point of 172.0° C., aFourier Transform IR with a peak at 3283 cm⁻¹ (as supposed to 3257 cm⁻¹and 3306 cm⁻¹ for Forms B and H respectively) and an XRPD pattern with astrong peak at 3.78±0.2 degrees 2θ.

U.S. Pat. No. 5,463,116 (“the '116 patent”) lists the methanolate,ethanolate, isopropanolate and acetonitrilate solvates of nateglinide.According to the '116 patent, amorphous nateglinide may be obtained bydrying the hydrate and the solvates. The hydrate may be crystallized bydissolving B-type crystals in a 1.5:1 mixture of ethanol and water,followed by crystallization, as disclosed in Example B-3 of the '116patent.

The present Applicants obtained a hydrate of nateglinide which theApplicants labeled as Form Z. However, repeating of Example B-3 orcomparative Example A3 of the '116 patent also results in Form Z, aswell as the crystallization procedure of the '484 patent. Form Z isobtained when only water is present, but Form E methanolate orethanolate when both methanol or ethanol and water are present.

WO 02/34713, a PCT publication in Japanese, provides in its abstract: “Aprocess for preparing B form nateglinide crystals containingsubstantially no H-form crystals, which comprises the step of drying wetcrystals of a nateglinide solvate at a low temperature until the solventdisappears and then causing them to undergo a crystal transition.”According to the Applicant's translation of Example 1 of the WOpublication: “Nateglinide H-form crystals (24.5 kg) were added toethanol (360 L) and stirred to dissolution at room temperature. Afterdissolution was confirmed (the mixture) was cooled to 5° C. and allowedto mature at 5° C. for one hour. The deposited crystals were separatedand damp crystals (43.0 kg) obtained. These were dried at 45° C. in arack drier for 24 hours (water content ca. 1%) and then heated for 12hours at 90° C. to bring about a crystal transformation, when drycrystals (13.3 kg) were obtained. When these crystals were measured byDSC, the characteristic B-form peak was detected (mp ca. 130° C.) butthe characteristic H-form peak (mp ca. 139° C.) was not detected. Hencethe crystals obtained were of the B-form only and the H-form wasconcluded to be essentially absent.”

According to the Applicants' translation of Page 3, Line 2 of the WOpublication: “The moist solvate crystals obtained (BS: from the cooledsolution) are dried till the solvent disappears. The temperature forthis will differ depending on the type and quantity of solvent, butusually lies below 60° C. and preferably below 50° C. Although there isno lower limit to the temperature, [the drying] is usually carried outat 20° C. or more for economic reasons. Drying is favorably carried outat usual reduced pressure; at industrially attainable reduced pressuresthe drying will be complete in a short time. Though the drying at lowtemperature can be continued to virtual disappearance of the solvent itis not necessary to clear it completely. Even if solvent to the extentof 5% by weight is present this is no problem because it will disappearduring the crystal transformation. By heating the dried crystals at60-110° C., preferably 70-100° C., a crystal transformation into theB-form is brought about. Though the crystal transformation is usuallyfavorably carried out in 0.5 to 48 hours, a period of 1-24 hours is mostfavored.”

Another PCT publication, WO 03/022251 discloses a crystalline form ofnateglinide labeled “AL-type”. The crystalline form is characterized ashaving a melting point of 174-178° C., an XRPD pattern with peaks at7.5, 15.5, 19.8 and 20.2 degrees 2θ, and an infra red spectrum withabsorption bands in the region 1711.5, 1646.5, 1538.7, 1238.8, 1215.1and 700.5 cm⁻¹. The crystalline form is obtained in the examples from asolution of acetonitrile under a specific temperature range.

Processes for preparation of nateglinide are disclosed in WO/0232854.

The discovery of new polymorphic forms of a pharmaceutically usefulcompound provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic. New polymorphic formsof nateglinide have now been discovered.

SUMMARY OF THE INVENTION

The present invention provides for 26 crystalline forms of nateglinide,denominated Forms A, C, D, F, G, I, J, K, L, M, N, O, P, Q, T, U, V, Y,α (alpha), β (beta), γ (gamma), δ (delta), ε (epsilon), σ (sigma), θ(theta) and Ω (omega).

Some of these crystalline forms have bound solvents, that is solventsthat are part of the crystalline structure (solvates). These solvateshaving bound solvent include Form A (xylene), C(dimethylacetamide—“DMA”), D (ethanol—“EtOH”), E (ethanol andmethanol—“MeOH”), F (n-propanol—“n-PrOH”), G (isopropyl alcohol—“IPA”),I (n-butanol—“n-BuOH”), J (N-methylpyrrolidone—“NMP”), K(dimethylformamide—“DMF”), M (carbon tetrachloride—“CTC”), N(dichloroethane—“DCE”), O (methanol), Q (chloroform—“CHCl₃”), T(methanol), V (dimethoxyethane—“DME”), Y (chloroform; dichloromethane),β (N-methylpyrolidone), γ (N-methylpyrolidone) and ε (acetone;acetonitrile—“MeCN”; nitromethane—“NM”) and θ (heptane). Form Z is ahydrate, having water in the crystalline structure. Form Ω is a solvateof both water and isopropyl alcohol.

Other crystalline forms do not have bound solvents, i.e., less thanabout 2% as measured by loss on drying (“LOD”), and are anhydrates.These anhydrates include crystalline Forms L, P, U, α, δ and σ.

The XRPD pattern of these forms as substantially depicted is disclosedin FIGS. 1-27 and 63, with the characteristic peaks listed in Table I.The DSC thermograms for the forms is disclosed in FIGS. 36 to 62, andthe characteristic DSC peaks are listed in Table II. The FTIR spectrumof the anhydrate and hydrate Forms and their characteristic peaks arealso provided. The LOD values from the TGA analysis of some of theseForms is listed in Table III. Preparation of the various Forms bycrystallization procedure is listed in Table IV, while preparation bytrituration is listed in Tables V and VI, data on absorption of solventvapors is listed in Table VII, data on preparation by solvent removal islisted in Table VIII and data on crystallization from asolvent/anti-solvent system is listed in Tables IX-XI. FIG. 28summarizes the thermal stability of the various forms.

The present invention also provides for pharmaceutical formulations ofthe various crystalline forms and their administration.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an XRPD pattern for nateglinide Form A.

FIG. 2 is an XRPD pattern for nateglinide Form C.

FIG. 3 is an XRPD pattern for nateglinide Form D.

FIG. 4 is an XRPD pattern for nateglinide Form E.

FIG. 5 is an XRPD pattern for nateglinide Form F.

FIG. 6 is an XRPD pattern for nateglinide Form G.

FIG. 7 is an XRPD pattern for nateglinide Form I.

FIG. 8 is an XRPD pattern for nateglinide Form J.

FIG. 9 is an XRPD pattern for nateglinide Form K.

FIG. 10 is an XRPD pattern for nateglinide Form L.

FIG. 11 is an XRPD pattern for nateglinide Form M.

FIG. 12 is an XRPD pattern for nateglinide Form N.

FIG. 13 is an XRPD pattern for nateglinide Form O.

FIG. 14 is an XRPD pattern for nateglinide Form P.

FIG. 15 is an XRPD pattern for nateglinide Form Q.

FIG. 16 is an XRPD pattern for nateglinide Form T.

FIG. 17 is an XRPD pattern for nateglinide Form U.

FIG. 18 is an XRPD pattern for nateglinide Form V.

FIG. 19 is an XRPD pattern for nateglinide Form Y.

FIG. 20 is an XRPD pattern for nateglinide Form Z.

FIG. 21 is an XRPD pattern for nateglinide Form α.

FIG. 22 is an XRPD pattern for nateglinide Form β.

FIG. 23 is an XRPD pattern for nateglinide Form γ.

FIG. 24 is an XRPD pattern for nateglinide Form δ.

FIG. 25 is an XRPD pattern for nateglinide Form ε.

FIG. 26 is an XRPD pattern of nateglinide Form σ.

FIG. 27 is an XRPD pattern of nateglinide Form θ.

FIG. 28 is a thermal stability chart showing transformation of the formsduring drying, and is a summary of a comparison between the wet and thedry forms illustrated in various tables in the present invention.

FIG. 29 is an FTIR spectrum of nateglinide Form L.

FIG. 30 is an FTIR spectrum of nateglinide Form P.

FIG. 31 is an FTIR spectrum of nateglinide Form U.

FIG. 32 is an FTIR spectrum of nateglinide Form Z.

FIG. 33 is an FTIR spectrum of nateglinide Form α.

FIG. 34 is an FTIR spectrum of nateglinide Form δ.

FIG. 35 is an FTIR spectrum of nateglinide Form σ.

FIG. 36 is a DSC thermogram of nateglinide Form A.

FIG. 37 is a DSC thermogram of nateglinide Form D.

FIG. 38 is a DSC thermogram of nateglinide Form E.

FIG. 39 is a DSC thermogram of nateglinide Form F.

FIG. 40 is a DSC thermogram of nateglinide Form G.

FIG. 41 is a DSC thermogram of nateglinide Form I.

FIG. 42 is a DSC thermogram of nateglinide Form J.

FIG. 43 is a DSC thermogram of nateglinide Form K.

FIG. 44 is a DSC thermogram of nateglinide Form L.

FIG. 45 is a DSC thermogram of nateglinide Form M.

FIG. 46 is a DSC thermogram of nateglinide Form N.

FIG. 47 is a DSC thermogram of nateglinide Form O.

FIG. 48 is a DSC thermogram of nateglinide Form P.

FIG. 49 is a DSC thermogram of nateglinide Form Q.

FIG. 50 is a DSC thermogram of nateglinide Form T.

FIG. 51 is a DSC thermogram of nateglinide Form U.

FIG. 52 is a DSC thermogram of nateglinide Form V.

FIG. 53 is a DSC thermogram of nateglinide Form Y (chloroform solvate).

FIG. 54 is a DSC thermogram of nateglinide Form Y (dichloromethanesolvate).

FIG. 55 is a DSC thremogram of nateglinide Form Z.

FIG. 56 is a DSC thermogram of nateglinide Form α.

FIG. 57 is a DSC thermogram of nateglinide Form β.

FIG. 58 is a DSC thermogram of nateglinide Form δ.

FIG. 59 is a DSC thermogram of nateglinide Form ε.

FIG. 60 is a DSC thermogram of nateglinide Form γ.

FIG. 61 is a DSC thermogram of nateglinide Form σ.

FIG. 62 is a DSC thermogram of nateglinide Form θ.

FIG. 63 is a XRPD pattern of nateglinide Form Ω.

FIG. 64 is a determination of purity of Form B prepared by Example 15.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides for 26 crystalline formsof nateglinide (“NTG”), denominated Form A, C, D, F, G, I, J, K, L, M,N, O, P, Q, T, U, V, Y, α, β, γ, δ, ε, σ, θ and Ω. These crystallineforms are characterized by their XRPD pattern, DSC thermogram and TGAanalysis, among others. Also provided are processes for preparation ofother polymorphic forms such as Form B, E, H, S and Z.

The various crystalline forms are characterized by their XRPD pattern,which differs from one polymorph to another. Form E is rather similar byXRPD to Form Z, although some differences may be observed. The peak at3.7 is characteristic of Form E and is not observed in the XRPD of FormZ. The pattern in the range of 19-22 degrees two theta is also somewhatdifferent between these two forms. Table I lists the most characteristicpeaks for the new crystalline forms. The XRPD patterns are illustratedin FIGS. 1-27 and 63.

TABLE I XRPD characteristic peaks for the nateglinide crystalline formsCrystal Form Characteristic XRD peaks- Within about ±0.2 degrees twotheta A 6.6, 13.3, 13.9, 16.8, 27.2, 28.0 (FIG. 1) C 5.2, 8.2, 8.8 (FIG.2) D 6.6, 7.5, 13.1, 16.5, 17.4, 21.1 (FIG. 3) E 3.7, 4.6, 14.9, 15.6,16.1 (FIG. 4) F 4.8, 5.3, 15.2, 18.9, 19.6 (FIG. 5) G 14.4, 15.3, 19.3,20.3 (FIG. 6) I 5.5, 7.4, 16.8 (FIG. 7) J 8.0, 11.2, 12.0, 15.9, 16.1,17.7, 28.1 (FIG. 8) K 9.5, 15.4, 17.1, 21.2 (FIG. 9) L 17.6, 17.9, 19.6(FIG. 10) M 16.2, 16.4, 17.0, 17.8, 18.6, 19.4, 19.6 (FIG. 11) N 5.3,5.5, 8.9, 9.9, 20.4, 21.1 (FIG. 12) O 4.4, 5.2, 15.7, 16.6 (FIG. 13) P4.0, 4.6, 13.4, 13.9, 19.1 (FIG. 14) Q 5.1, 5.6, 16.2, 19.8 (FIG. 15) T7.2, 7.9, 8.3, 10.7 (FIG. 16) U 4.7, 7.4, 13.8, 17.0 (FIG. 17) V 4.5,5.8, 11.4, 16.4 (FIG. 18) Y 6.1, 14.2, 15.1, 18.7 (FIG. 19) Z 4.7, 5.3,13.5, 13.9, 15.1, 15.7, 16.1, 18.7, 19.5, 21.5 (FIG. 20) α 4.8, 5.1,19.0, 19.4, 27.7, 28.9, 31.2 (FIG. 21) β 4.6, 9.4, 13.9, 18.8 (FIG. 22)γ 4.4, 8.9, 18.4, 18.8, 19.5 (FIG. 23) δ 5.6 14.5, 18.2, 18.9, 19.5(FIG. 24) ε 4.2, 13.0, 13.6, 14.3, 16.2, 16.7, 19.6 (FIG. 25) θ 4.8,7.8, 15.5, 17.7 (FIG. 27) σ 5.5, 6.1, 6.7, 14.3 (FIG. 26) Ω 4.5, 7.8,15.5, 16.9, 17.8, 19.2, 19.7 (FIG. 63)

The various crystalline forms of nateglinide are also characterized bytheir DSC thermograms. Table II lists the DSC peaks (endotherms). Inaddition to the peaks listed in Table II, many of the variouscrystalline forms show an exotherm at about 165° C. followed by anendotherm at about 174° C., probably due to recrystallization intoS-Type Form.

TABLE II DSC peaks of the nateglinide crystalline forms Crystal Form DSCPeaks (° C.) A (FIG. 36) 70  98 138 — D (FIG. 37) 66 130 — — E (FIG. 38)75  86 104 129 F (FIG. 39) 53 103 128 — G (FIG. 40) 106 127 — — I (FIG.41) 46 121 — — J (FIG. 42) 49 105 168 — K (FIG. 43) 79 105 145 170 L(FIG. 44) 131 138 — — M (FIG. 45) 90 102 128 — N (FIG. 46) 77 100 130137 O (FIG. 47) 106 126 137 — P (FIG. 48) 106 113 (exotherm) 128 — Q(FIG. 49) 102 126 — — T (FIG. 50) 68 106 130 — U (FIG. 51) 128 138 — — V(FIG. 52) 81 139 — — Y dichloromethane solvate 122 130 — — (FIG. 54) Z(FIG. 55) 90  95 α (FIG. 56) 129 — — — β (FIG. 57) 91 100 — — γ (FIG.60) 93 136 — — δ (FIG. 58) 100 107 (exotherm) 130 — ε (FIG. 59) 64 108129 — σ (FIG. 61) — — — 127 θ (FIG. 62) 70 104 115 130 (exo)

The various crystalline forms are also analyzed by Thermal GravimetricAnalysis (TGA). TGA measurements show that Forms A, D, E, F, G, I, J, K,M, N, O, Q, T, U, V, Y, Z, β, γ, ε, θ and Ω contain significant amountsof bound solvents and may be considered as solvated forms ofnateglinide. The XRPD analysis of some of these solvated forms show thatsome of them are unstable when left in an open bottle for 24 hours. Incontrast to the above listed forms, TGA profiles of forms L, P, U, α, δand σ show no significant weight loss. These polymorphic forms ofnateglinide are free of bound solvents, i.e., less than about 2% LOD.Table III lists the solvents used for the preparation for nateglinidesolvated forms, as well as LOD values based on TGA analysis.

The ethanol solvate of nateglinide disclosed herein has an ethanolcontent of from about 10% to about 30% by weight. The ethanol solvate ofnateglinide ethanol solvate is represented by formula NTG·3/2 EtOH.Specifically, the solvate is nateglinide Form D.

The methanol solvates of nateglinide disclosed herein have a methanolcontent of from about 2 to about 60% by weight. Specifically,nateglinide methanol solvate exists as nateglinide Form E, Form O andForm T methanol solvate. Nateglinide methanol solvate is represented bythe formula NTG*1/4 MeOH (Form O) or by the formula NTG*1/2 MeOH (formE). Nateglinide Form T contains more than about 20% methanol by weight.The methanol content of Form T is from about 20% to about 60% by weight.

The isopropyl solvate of nateglinide disclosed herein has an isopropylalcohol content of from about 12% to about 30% by weight. Specifically,isopropyl solvate of nateglinide exists as nateglinide Form G.

A hydrate of nateglinide, Form Z, has a water content of about 10 toabout 50%, more preferably about 10% to about 40%, and most preferablyfrom about 15% to about 25%, measured either by the Karl Fischer methodor LOD. Form Ω, is a hydrate-solvate of isopropanol and contains about50% LOD water and isopropanol.

The heptane solvated form of nateglinide, Form θ, has about 7 to about8% heptane by weight, and is represented by the formula NTG∘ 1/4Heptane.

TABLE III LOD values by TGA and solvents used for the preparation ofnateglinide solvated forms LOD by TGA Crystal Form Solvent (weight %)Comments A Xylene 80 Storage at RT for 24 h is results in a partialconversion to Form B C DMA >5 D Ethanol 25 E MeOH  4 F n-PrOH 16-24 GIsopropyl Alcohol 22-28 I n-BuOH 20 Storage at RT for 24 h results in aconversion to Form L J N-Methyl Pyrolidone 2-3 XRD pattern slightly upto 100° C. changed after storage at RT sharp weight loss at forovernight 100° C. K Dimethyl formamide 34 M Carbon tetra chloride  2 NDichloroethane  8 O MeOH  2 Q Chloroform 10 Storage at RT for 24 hresults in a conversion to Form Y, which contains chloroform. TMeOH >20   Storage at RT for 24 h results in a conversion to Form E VDimethoxyethane  8-16 A sharp weight loss step of 7-8% is observed at70° C. Y Dichloromethane/ 2-8 Chloroform Beta N-Methyl Pyrolidone GammaN-Methyl Pyrolidone — No significant weight loss up to 90° C. Sharpweight loss at 90° C. Epsilon Acetone/ Above 4 Nitromethane/Acetonitrile Theta Heptane 7.4% Omega IPA and Water  50%

The anhydrate forms and the hydrated Form Z, are also characterized bytheir FTIR spectrum. Form Z is characterized by a FTIR spectrum (FIG.32) with peaks at about 699, 1542, 1645, 1697, 2848, 2864, 2929, 3269and 3504 cm⁻¹. The more characteristic peaks are observed at about 1645,1697, 3279 and 3504 cm⁻¹. Characteristic FTIR peaks are for theanhydrates, specifically Forms L, U, P, α, δ and σ are disclosed in thefollowing table.

nateglinide form Characteristic FTIR Peaks Form Alfa: 3283, 1711, 1646,1420, 1238 cm⁻¹ (FIG. 33) Form L: 1741, 1726, 1621, 1600, 1538, 1211,1191 cm⁻¹ (FIG. 29) Form U: 3350, 1701, 1646, 1291 cm⁻¹ (FIG. 31) Formδ: 3306, 1729, 1704, 1275 cm⁻¹ (FIG. 34) Form σ 3303, 1705, 1640 cm⁻¹(FIG. 35) Form P: 3309, 1748, 1589 cm⁻¹ (FIG. 30)

The various crystalline forms are related to each other in that dryingof one form may result in a transformation to another form, namelynateglinide Forms A, B, D, E, F, G, H, I, J, K, L, M, N, Q, S, T, V, Z,α, β, δ, γ, ε, θ and Ω. The drying is carried out by heating a sampleunder ambient or reduced pressure. Generally, a preferred temperature isfrom about 40° C. to about 80° C., more preferably under reducedpressure. Of these forms, Forms B, H, L, U and sigma are thermallystable, and do not convert to another form upon heating. Many of theabove forms convert to Form B upon drying, namely Forms A, C, D, E, F,G, J, K, P, Q, T, Z, α, β, δ, θ and Ω. Of these forms, Form α, δ, Y andO are somewhat stable, and usually retain their crystalline structureafter heating, unless heated to a high temperature. For example, Form δis stable when heated to 60° C. overnight (at least about 8 hours), butheating of Form δ at 120° C. and 1 atmosphere results in Form B. Thus,heating at a temperature above about 80° C. may cause a transformationin these forms. The term “stable” as used herein refers to a polymorphicchange of less than about 5% by weight, more preferably less than about2%, particularly for Form δ.

The conversion of some of the forms to Form B goes through another form.For example, the conversion of Form Ω and E to Form B may go throughForm Z.

Form G may represent a link between Forms F, T on the one hand, and FormB on the other hand. Forms T and F, upon drying, convert to a mixture ofForm B and G, which makes is probable that Forms F and T convert to FormB by going through Form G.

Of the forms that convert to Form B, some of them sometimes under dryingconvert to other forms. Form K may convert to Forms α or S, while Form Cmay convert to Form B or α. Form α may convert to Form S upon heating,but the presence of seeds of Form B in the sample of Form α results inForm B. Probably Forms C and K transform to Form α first, and that it isthrough Form α that they transform to Form B or S. Form J may convert toForm B or β, though its conversion to Form B may go through Form β. TheForm J used in preparing Form β is preferably obtained bycrystallization from N-methylpyrrolidone. When Form J contains someseeds of Form γ, heating results in Form γ.

The acetonitrile solvate of Form Epsilon, when dried, results in Form B.While the nitromethane solvates of Form Epsilon when dried result inForms H or P. When Form P is dried, Form H is obtained, which makes itprobable that conversion of Form Epsilon to Form H goes through Form P.

Another thermally stable Form of nateglinide is Form L. Form L may beobtained by heating Forms M, N and D. To obtain Form L, these variousforms are preferably heated for about 3-10 hours at a preferredtemperature range of from about 40° C. to about 80° C., more preferablyabout 50° C. under reduced pressure. Form γ may also be prepared byheating Form J containing seeds of Form γ under similar conditions.

Another thermally stable form of nateglinide is Form H which may beprepared by heating nateglinide Forms P, V and ε. Form S may be preparedby heating Forms α and K, though the transition of Form K to Form S maygo through Form α.

Form U is another thermally stable Form of nateglinide, and does notundergo a transition after being heated at about 100° C. for at leastabout 8.5 hours.

Storage at room temperature and pressure may also cause a transition ofone form to another. Form A partially converts to Form B during storageat room temperature for about a day. Form I converts to Form L under thesame conditions. Also under the same conditions, Form Q converts to FormY (containing chloroform), while Form T converts to Form E.

Form α is related to Forms F, G, I and ε in that it may be crystallizedout of the same solvent as those forms, n-propanol, isopropyl alcohol,n-butanol and acetonitrile, respectively. Form α however is crystallizedunder different conditions, see e.g., Table IV. Form α is often obtainedwith prolonged crystallization step (at least about 2-3 days). Not beingbound by any theory, this phenomenon may point to a possible conversionof another crystalline form, such as those obtained from the samesolvent, to Form α overtime in the solvent.

Forms E and D are also related in that both of the forms may becrystallized out of ethanol; but these forms crystallize under differentconditions, see e.g., Table IV. The crystallization of Form E in ethanolis prolonged, for at least about 5 days, more preferably at least about1 month. Not being bound by any theory, it might be possible thatinitially Form D crystallizes out, followed by a conversion to Form Eovertime in the solvent.

To prepare Form S, the wet sample obtained after crystallization has tobe dried. Crystallization from a solution of nateglinide in n-butanoland DMF results in a solvate, which needs to be dried to obtain Form S.The wet samples are nateglinide Forms K, I and alpha.

Some of the forms may first appear as a gel, and then transform intocrystals during the filtration step (e.g. form epsilon fromnitromethane, and form A from xylene) or overtime (e.g. Form M fromcarbon tetrachloride and Form J from N-methylpyrrolidone). Generally,gels are unstable forms which crystallize over time.

Some of the crystalline forms may be obtained by trituration. As usedherein, trituration refers to obtaining a solid from a mixture ofnateglinide in a solvent without complete dissolution. A form ofnateglinide is mixed in a particular solvent and agitated for asufficient time to allow for transformation to another crystalline form.After agitation, a suspension or a paste forms. A solid may then beseparated from the suspension by techniques well known in the art, suchas filtration. The paste may be filtered, to name one technique, toremove excess solvent. The result of this trituration procedure isvarious forms of nateglinide.

The trituration of Form delta in water may result in Form Z after about5 hours, and Form E after about 8 hours, which may also point to atransition of Form Z to Form E. All three forms may be heated to obtainForm B.

Some of the crystalline forms may be obtained by solvent removal. Firsta solution of nateglinide in a suitable solvent is prepared. The solventmay be heated to obtain a clear solution. The solvent may be heated fromabout 40° C. to about 70° C., with about 55° C. being preferred. Thesolvent is then removed to obtain a residue, preferably at elevatedtemperature within the said range. The solvent is preferably removed byevaporation, with evaporation under reduced pressure being particularlypreferred. The resulting residue is then examined. Suitable solventsinclude esters, ketones, amines, amides, alcohols and nitrites. Removalof acetonitrile, acetone, ethyl acetate and isopropyl alcohol assolvents results in nateglinide Form B.

Some of the crystalline forms are obtained by absorption of solventvapors. Nateglinide is contacted with vapors of a particular solvent,resulting in absorption of the solvent. Absorption of ethanol results inForm D, methanol in Form O, and DCM in Form Y. Form H was stable in thepresence of vapors of water and acetone.

Some of the crystalline forms may be obtained by crystallization from asuitable solvent. Form omega is obtained by crystallization ofnateglinide out of a mixture of water and isopropanol. Preferably, theratio of the water to isopropanol is from about 1/2 to about 1/5, morepreferably 1/3 (vol/vol).

Nateglinide Form Z is generally prepared by acidification of a solutionof an alkali metal or alkaline earth metal salt of nateglinide in anaqueous solvent. Preferred solvent is water free of a co-solvent.Preferred salts are sodium and potassium salts, with the sodium saltbeing most preferred. Before acidification, the solution preferably hasa pH of above about 8, while after acidification, the pH is preferablefrom about 1 to about 5, most preferably from about 2 to about 5.Acidification results in precipitation of nateglinide, which may berecovered by techniques well known in the art, such as filtration.

Nateglinide Forms B and U may be prepared by crystallization from anorganic solvent such as ethyl acetate or acetone. In the procedure forthe preparation of form B, crystallization is preferably induced byconcentration of the solvent, while for Form U, by seeding of thesolution.

Nateglinide Forms B, H, U, Z, δ, θ and σ are related in that all of themmay be prepared from a two solvent system. The two solvent system usedis a mixture of a solvent and an anti-solvent. Example of suitableantisolvents are C₅ to C₁₂ aromatic hydrocarbons such as toluene andxylene, and C₅ to C₁₂ saturated hydrocarbons such as hexane and heptane.Examples of suitable solvents are C₁ to C₅ alcohols such as methanol,ethanol, isopropanol, n-butanol and n-propanol, lower ketones (C₃ to C₆)such as acetone and lower esters (C₃ to C₆) such as ethyl acetate. Aftercrystallization, the crystals are recovered by techniques well known inthe art, such as filtration and centrifugation, and may be dried. Todry, the temperature may be increased or the pressure reduced. In oneembodiment, the crystals are dried at about 40° C. to 60° C., at apressure of less than about 50 mmHg.

When nateglinide is crystallized out of a binary mixture, particularlyin the absence of stirring, the crystalline product is often Form B, asillustrated in Table IX. The binary mixture is prepared by suspendingnateglinide in the anti-solvent, and then adding the solvent to form asolution. Nateglinide Form B may be obtained at differentcrystallization temperatures, such as at room temperature and at about0° C., particularly in the absence of stirring.

Crystallization from a binary mixture of the above solvents andanti-solvents may lead to other forms of nateglinide other than Form B.Crystallization out of a toluene/methanol mixture may result innateglinide Form E, which may be converted to Form B by heating.Additionally, a heptane/ethyl acetate combination may sometimes lead toa mixture of Forms B and Z, especially with longer period ofcrystallization (over about 3 days), while a toluene/ethyl acetatemixture may result in a mixture of Form B and H. A mixture of Form B andZ may be converted to one containing substantially Form B throughheating, since Form Z converts to Form B through heating.

In another embodiments, rather than preparing a solution by firstsuspending nateglinide in the anti-solvent, a solution is prepared inthe solvent, followed by combining with the anti-solvent. The combiningis carried out in this embodiment in such a way where upon additon asolution is formed, and any precipitated solids go back into solution.Preferrably, the anti-solvent is heated so that upon mixing of thesolution and the anti-solvent, immediate precipitation does not takeplace.

The different forms may be obtained depending on thesolvent/anti-solvent ratio, crystallization conditions and the time ofstirring. Generally, Form Z is crystallized from an ethylacetate/heptane ratio of about 2 to 4, form H a ratio of about 4 toabout 7, Form B a ratio of about 6 to about 8, Form U a ratio of about 1to about 2, Form θ a ratio of about 1 and Form δ a ratio of about 1 toabout 8, more preferably from about 1 to about 2 (vol/vol).

Of these, some forms may crystallize as other forms, and convert afterbeing stirred for a sufficient time in the solvents. Stirring theresulting slurry from crystallization at a temperature of from about−15° C. to about 10° C., preferably about 5° C., may result in Form δ.Form δ seems to result from stirring of forms such as Form U, Form θ,Form H and even Form B. Preferably the stirring to obtain Form δ iscarried out for at least about 2-3 hours, more preferably for at leastabout 10 hours.

Other than a solvent:antisolvent ratio of about 1, formation of Form θseems to be favored at lower crystallization and filtering temperatures,from about −15° C. to about 10° C. preferably 5° C. As previously noted,stirring of Form θ, preferably at the specified temperature range,results in Form δ.

Form U may be obtained by stirring with Form B or H in an organicsolvent. Stirring for about 1 hour is sufficient to obtain Form U.However, additional stirring, such as above about 5 hours, may result ina transition to Form δ. Form U may also be obtained by crystallization,preferably at the specified ratio, more preferably at a crystallizationand filtering temperature of about −15° C. to about 10° C. Form U isgenerally favored when starting with a temperature of from about 25° C.to about 35° C., followed by cooling in less than about 1 hour to atemperature of from about 0° C. to about 10° C., with about 5° C. beingpreferred, followed by filtering in less than about 1 hour. Highersolvent to anti-solvent ratio may favor form U over θ.

Form H may be obtained under both low and high crystallizationtemperatures, preferably under the specified solvent/anti-solvent ratio.Form B, on the other hand, tends to crystallize at a temperature of atleast about 15° C.

Forms Z generally crystallizes after about a day at a finalcrystallization temperature of at least about 15° C., more preferablyfrom about 15° C. to about 30° C., and most preferably from about 20° C.to about 25° C. The initial crystallization temperature for these formsis preferably above 35° C., followed by cooling in a few hours, morepreferably about 1 hour, to about 20° C. to about 25° C. Theseconditions may lead to Form Z, which converts to Form B by drying.

Form σ may also be obtained by stirring of crystals of Form B. Not beingbound by any theory, it may be possible that Form σ is obtained throughForm U, that is stirring results in a transition of Form B to Form Ufollowed to Form σ. Prolonged crystallization and filtration ispreferred for obtaining Form σ, i.e., preferably at least about 10hours.

Table X does not show a transition of Form B to other forms despiteprolonged stirring in the anti-solvent/solvent system due to use of ahigh ratio of ethyl acetate. Preferably about a 1:1 ratio of solvent toanti-solvent is used for obtaining other forms through stirring of FormB in a solvent/antisolvent mixture.

The results of the processes may vary when precipitating a solid aftercombining the solution and the anti-solvent. In this embodiment, thesolution is combined with the anti-solvent in such a way to result inprecipitation, in contrast with the other embodiments that result in asolution after the combining step. To cause substantial precipitation,preferably, the solution is combined with a cold anti-solvent. Morepreferably, the antisolvent is from about 20° C. to about 40° C. colderthan the solution, particularly when an ethyl acetate/heptane system isused. Most preferably, the heptane has a temperature of from about 0° C.to about 10° C. and the ethyl acetate a temperature of from about 30° C.to about 40° C.

In this embodiment, Form U may be obtained within a wide range ofsolvent/anti-solvent ratios and crystallization temperatures. Forexample, table XI shows that Form U may be obtained from a solvent toanti-solvent ratio of from about 1 to about 6, and final crystallizationtemperatures from about 0° C. to about 30° C. Not being bound by anytheory, the presence of other forms, particularly Form δ and σ,especially after long crystallization step, points to possible atransition of Form U to these forms. The presence of a mixture of Form Band U after 1 hour also points to the possibility that Form B might beimmediately crystallized out of the solution, followed by a transitionto Form U, which itself may change overtime to Forms δ or σ.

The following table provides guidance on obtaining Forms B, H, U, Z, δ,θ and σ from a solvent:anti-solvent system:

V/V ratio Crystal (EA/Heptane) Filtration temp. form (about) (about)obtained 1:1 15° C.-30° C. No stirring B preferably 20-25° C. 1:1 15°C.-30° C. With stirring Immediately after crystallization B preferably20-25° C. Stirring for at least about 21 h σ 1:1 15° C.-30° C.Precipitation Immediately after crystallization B preferably 20-25° C.without going Stirring for at least about 1 h U into solution aftercombining 1:1 −15° C.-10° C. Immediately after crystallization Dryingpreferably 5° C. θ → B Stirring at about 5° C. δ 1.5:1 −15° C.-10° C.Immediately after crystallization U preferably 5° C. Stirring at about5° C. δ 2:1-8:1 −15° C.-10° C. Immediately after crystallization H (95%preferably 5° C. yield) Stirring for about 1-5 h U Stirring for at leastabout 5 h δ 2:1-8:1 15° C.-30° C. Wet crude Drying preferably 20-25° C.material Z → B 2:1-8:1 15° C.-30° C. Dry crude H preferably 20-25° C.material

Depending on the preparation procedure, nateglinide Form δ may containfrom about 0.5% to about 3% of residual heptane by weight. The removalof heptane without changing the crystal form may be carried out in afluidized bed drier, preferably at a temperature of from about 60 toabout 70° C., more preferably for at least about 3 hours. The residualHeptane may be also removed under stirring, preferably at a temperatureof at least about 40° C. under vacuum. The δ Form is preferablypolymorphically pure and contains less than about 5% Form H (wt/wt),more preferably less than about 2% (wt/wt), and most preferably lessthan about 0.5% (wt/wt).

Crystalline Form δ is stable at a temperature of about 40° C. and arelative humidity of about 75% for at least about 3 months.

Trituration of Form δ in ethyl acetate may result in other polymorphicforms of nateglinide. Triturating nateglinide Form δ at a temperature offrom about 20 to about 30° C. in ethyl acetate results in Form U, whiletriturating at higher temperatures (above 40° C.), such as at about 50°C., results in Form B.

The processes of the present invention allow for obtaining Forms δ and Bwith a purity of at least about 95%, more preferably at least about 98%wt/wt compared to other polymorphic forms. These forms may be producedparticularly free of the H Form.

The starting material used for the processes of the present inventionmay be any crystalline or amorphous form of nateglinide, includingvarious solvates and hydrates. With crystallization processes, thecrystalline form of the starting material does not usually affect thefinal result. With trituration, the final product may very depending onthe starting material. One of skill in the art would appreciate themanipulation of the starting material within skill in the art to obtaina desirable form with trituration.

The processes of the present invention may also be practiced as the laststep of prior art processes that synthesize nateglinide.

Many processes of the present invention involve crystallization out of aparticular solvent, i.e., obtaining a solid material from a solution.One skilled in the art would appreciate that the conditions concerningcrystallization may be modified without affecting the form of thepolymorph obtained. For example, when mixing nateglinide in a solvent toform a solution, warming of the mixture may be necessary to completelydissolve the starting material. If warming does not clarify the mixture,the mixture may be diluted or filtered. To filter, the hot mixture maybe passed through paper, glass fiber or other membrane material, or aclarifying agent such as celite. Depending upon the equipment used andthe concentration and temperature of the solution, the filtrationapparatus may need to be preheated to avoid premature crystallization.

The conditions may also be changed to induce precipitation. A preferredway of inducing precipitation is to reduce the solubility of thesolvent. The solubility of the solvent may be reduced, for example, bycooling the solvent.

In one embodiment, an anti-solvent is added to a solution to decreaseits solubility for a particular compound, thus resulting inprecipitation. Another way of accelerating crystallization is by seedingwith a crystal of the product or scratching the inner surface of thecrystallization vessel with a glass rod. Other times, crystallizationmay occur spontaneously without any inducement. The present inventionencompasses both embodiments where crystallization of a particular formof nateglinide occurs spontaneously or is induced/accelerated, unless ifsuch inducement is critical for obtaining a particular form.

Nateglinide of defined particle size may be produced by known methods ofparticle size reduction starting with crystals, powder aggregates andcourse powder of the new crystalline forms of nateglinide. The principaloperations of conventional size reduction are milling of a feedstockmaterial and sorting of the milled material by size.

A fluid energy mill, or micronizer, is an especially preferred type ofmill for its ability to produce particles of small size in a narrow sizedistribution. As those skilled in the art are aware, micronizers use thekinetic energy of collision between particles suspended in a rapidlymoving fluid stream to cleave the particles. An air jet mill is apreferred fluid energy mill. The suspended particles are injected underpressure into a recirculating particle stream. Smaller particles arecarried aloft inside the mill and swept into a vent connected to aparticle size classifier such as a cyclone. The feedstock should firstbe milled to about 150 to 850 μm which may be done using a conventionalball, roller, or hammer mill. One of skill in the art would appreciatethat some crystalline forms may undergo a transition to another formduring particle size reduction.

Pharmaceutical compositions may be prepared as medicaments to beadministered orally, parenterally, rectally, transdermally, bucally, ornasally. Suitable forms for oral administration include tablets,compressed or coated pills, dragees, sachets, hard or gelatin capsules,sub-lingual tablets, syrups and suspensions. Suitable forms ofparenteral administration include an aqueous or non-aqueous solution oremulsion, while for rectal administration suitable forms foradministration include suppositories with hydrophilic or hydrophobicvehicle. For topical administration the invention provides suitabletransdermal delivery systems known in the art, and for nasal deliverythere are provided suitable aerosol delivery systems known in the art.

Pharmaceutical formulationss of the present invention contain anateglinide Form selected from A, C, D, F, G, I, J, K, L, M, N, O, P, Q,T, V, Y, α, β, γ, δ, ε, σ, θ and Ω. The pharmaceutical composition maycontain only a single form of nateglinide, or a mixture of various formsof nateglinide, with or without amorphous form. In addition to theactive ingredient(s), the pharmaceutical compositions of the presentinvention may contain one or more excipients or adjuvants. Selection ofexcipients and the amounts to use may be readily determined by theformulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelitinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dixoide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,nateglinide and any other solid excipients are dissolved or suspended ina liquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

The dosage and formulation of STARLIX may be used as a guidance. Thedosage used is preferably from about 30 to about 240 mg of nateglinide,more preferably from about 60 to about 120 mg of nateglinide. Thepharmaceutical compositions of the present invention, preferably in theform of a coated tablet, are administered from about 10 minutes to about1 hours prior to a meal, more preferably about 15 minutes before eachmeal. The dose is not taken if the meal is skipped. The pharmaceuticalcompositions may also be used in combination with metaformin.

Instruments

X-Ray Powder Diffraction:

X-Ray diffraction was performed on X-Ray powder diffractometer,Scintag®, variable goniometer, Cu-tube, solid state detector. Sampleholder: A round standard aluminum sample holder with round zerobackground quartz plate.

The sample was put on the sample holder and immediately analyzed as is.

-   Scanning parameters: Range: 2-40 deg 2θ, Continuos Scan, Rate: 3    deg./min.    DSC:-   DSC821^(e) Mettler Toledo®, Sample weight: 3-5 mg, Heating rate: 10°    C./min, Number of holes in the crucible: 3    TGA:-   Mettler TG50®, Sample weight: 7-15 mg, Heating rate: 10° C./min    FTIR:-   Perkin-Elmer®, Spectrum One FTIR spectrometer, Range: 4000-400 cm−1,    no. of scans: 16, resolution: 4.0 cm−1, DRIFT technique.

EXAMPLES Example 1 This Example Illustrates Preparation of Various Formsof Nateglinide from a Solution

Nateglinide (5 g) was placed into an erlenmeyer flask and heated to thespecified temperature. The solvent was added in 1-ml portions (in somecases, the solvent was added in 5-ml portions) until a clear solutionwas obtained. If a clear solution was not obtained after addition of 150ml of the solvent, the hot mixture was filtered.

The clear solution was left to crystallize at room temperature. Ifcrystallization did not happen or was poor, the solution wasrefrigerated at 3° C. The precipitate was filtered off (at RT or at 5°C. depending on the temperature of the crystallization), weighed anddivided into 2 equal parts. One part was dried at 50° C. under reducedpressure (20-30 mmHg) to constant weight (±0.01 g) for about 3-10 hours.Details are presented in Table IV.

TABLE IV Data on crystallization of NTG from a single solvent L/S, T,Time Time Form Form Solvent ml/g ° C. RT, h 3° C., h Wet Dry Xylene 3070 25 — A A >> B DMA  1 55 25 — C α EtOH  1 55 25 — D L EtOH  2* 54  6 42 D B MeOH  1 55 24 — E B EtOH  3 55 1 m 18 d E B n-PrOH  1 57 25 144F G + B n-PrOH  2 55 10 d  — α α n-PrOH  2 55  3 5 d α α IPA  1.2 57 25 48 G B IPA  3 55 1 m  20 α α NMP  1.4 57 73 — J B + β DMF  1.6 56 24 52 K S CTC 30 65 25 — M L DCE  2.2 55 23  47 N L CHCl₃  1 54 73 193 Q QDME  1.4 56 96 — V H n-BuOH  4 55 1 m  20 α S n-BuOH  1.4 57 25 144 I SAcetone  2 20 144   20 ε H NM 30 70 24 — ε P MeCN  8 55  3  20 ε ε + BMeCN 19 55 8 d — α α MeCN 19 55 7 d  5 α α DCM  2* 54 47 — Y Y EA  9 5522 — α α EA  9 55 10 d  5 d α α EA 15 55 9 d — α α EA 15 55 8 d 5 d α αLegend. L/S—liquid/solid ratio: *the solvent was added in 5-ml portions;T—starting temperature; Ww—weight of wet sample after filtration,Wd—weight of the sample after drying at 80-90° C./20 mbar. Solventabbreviations: MeOH—methanol, EtOH—ethanol, n-PrOH—n-propanol,IPA—2-propanol, n-BuOH—n-butanol, EA—ethyl acetate, NM—nitromethane,DMF—N,N-dimethylformamide, DMA—N,N-dimethylacetamide,NMP—N-methylpyrrolidone, MeCN—acetonitrile, Ether—diethyl ether,DME—dimethoxyethane, DCM—dichloromethane, DCE—1,2-dichloroethane andCTC—carbon tetrachloride.

Example 2 This Example Illustrates Trituration of Nateglinide Form H andU in Various Solvents

Nateglinide (5 g) was placed into an Erlenmeyer flask. Solvent was addedin 1-ml portions to prepare a stirrable mixture. The flask was stirredwith a magnetic stirrer at room temperature. A solid was filtered off atroom temperature, weighted, and divided into 2 equal parts. One part wasdried at 55° C. under 20-30 mm/Hg pressure to constant weight (±0.01 g).

Details are presented in Tables V and VI.

TABLE V Data on trituration of NTG with a single solvent Start L/S FormForm Form Solvent ml/g Time, h wet dry H MeOH 1.2 24 T G + B H EtOH 1.224 D B H IPA 1.2 24 G G + B H n- 1.2 23 F B PrOH H n- 1.4 24 I BuOH HMeCN 4.8 25 P H + P H NM 4 26 ε H + P H NMP 0.8 24 J β H DMF 1.2 25 K HDMA 1.2 26 C B H DME 1.4 24 V H H Dioxane 2.2 24 δ δ H THF 0.8 23 δ δ HDCM 1.8 25 Y Y H CHCl₃ 1 25 Q Q + B H DCE 1.8 24 Q + H Q + H

TABLE VI Data on trituration of NTG with a single solvent Start L/S FormForm Form Solvent ml/g Time, h wet dry U AcOH 1.8 24 H + S H + S U MeOH1.2 24 α α U EtOH 1.6 24 B + α B + α U IPA 1.8 24 G + S G + S U n- 1.425 F B PrOH U n- 1.6 26 α α BuOH U NM 5 24 P P U NMP 1 25 J + γ γ U DMF1 23 K α U DMA 1.2 24 C α U Acetone 2 24 P P U MEK 2.4 23 H + α H + S UMIPK 3 24 H + α H U MIBK 3.6 24 H + α H + S U DME 1.8 24 H + α H + S UDioxane 2 23 δ B U THF 0.8 23 δ δ + B U DCM 1.6 24 Y + S Y + S U CHCl₃1.2 25 δ δ U DCE 3.8 26 Q Q

Example 3 This Example Illustrates Absorption of Solvent Vapors byNateglinide

Nateglinide (3.50 g) was added to a polypropylene can and weighed. Thecan was introduced into a bigger polypropylene container containing asolvent, and stored at room temperature. The can was removed from thecontainer and weighed (Wfinal). The can content was divided into 2portions. One portion was dried at a temperature of 55° C. and apressure of 20-30 mmHg to constant weight (±0.01 g). Details arepresented in Table VII.

TABLE VII Data on absorption of solvent vapors with NTG Form H Form FormNTG W, g Brutto, g Solvent Time, d Wfinal Δ wet dry 3.50 15.77 EtOH 416.29 0.52 D B 3.50 15.94 MeOH 4 16.12 0.18 O O 3.50 15.78 Acetone 415.86 0.08 H H 3.49 51.86 DCM 4 51.90 0.04 Y — 3.50 15.27 Water 4 15.290.02 H H Legend. Brutto—starting weight of the can with NTG;Wfinal—final weight of the can with NTG after the exposure; Δ—overweight

Example 4 This Example Illustrates Preparation of Various Forms ofNateglinide by Solvent Removal

Nateglinide (5 g) was dissolved in the following solvents at about 55 Cin over about 15 minutes until a clear solution was obtained. Thesolvent was removed to dryness by evaporation at about 55 C/20-30 mmHgto give dry nateglinide.

TABLE VIII Data on solvent removal Solvent Form, dry MeCN B Acetone B EAB

Example 5 This Example Illustrates Preparation of Form Z

D-Phenylalanine (PheOH, 7.73 g) was treated with 3.5% NaOH (185 ml, 3.5equivalents), at room temperature to afford a clear solution of thecorresponding Na-salt. A solution of neattrans-4-isopropylcyclohexanecarboxyl chloride (IPCHAC, 9.02 g, 1.01equivalent) was added to the solution of Phe-OH obtained above, over 3minutes, while stirring at room temperature. The rest of the IPCHAC inthe funnel was washed with toluene (1 ml) and added. The resultingmixture was stirred for 1 hour, and was treated with 10% HCl (32 ml) toadjust the pH to 3, while stirring. The mixture was stirred for 1 hour,and filtered. The solid was washed with water (200 ml) and sucked wellto afford 33.3 g of the moist product, which lost weight after drying at78° C./2.2 mbar. Assay 98.4%, purity>99%, yield 86%.

Example 6 This Example Illustrates Preparation of Nateglinide byCrystallization from Binary Mixtures (Solvent/Anti-Solvent)

Nateglinide (5 g) and an anti-solvent (20 ml) were placed into anErlenmayer flask. The mixture was heated at about 55° C. over about 15minutes, followed by addition of solvent in 0.25-1 ml portions until aclear solution was obtained. The clear solution was left to crystallizewithout stirring at room temperature.

If crystallization did not happen or was poor after 24 hours, thesolution was refrigerated at 3-5° C. The precipitate was filtered off(at RT or at 5° C. depending on the temperature of crystallization) togive Form B. The wet material was dried at 50° C. under reduced pressure(20-30 mmHg) to give dry Form B.

TABLE IX Data on crystallization of NTG from binary solvents Ratio, L/S,Form Form Solvents v/v ml/g T_(cryst)., ° C.^(f) Time, h Ww, g Wd, g wetdry Toluene-  40:1 4.1 RT → 3 23/23 7.84 3.56 B B EtOH Toluene-  40:14.1 3 22/23 6.82 3.72 E B MeOH Toluene-IPA  27:1 4.15 RT → 3 22/24 7.833.28 — B Toluene-EA 4.2:1 4.95 RT 26 7.27 4.0 — B + H Toluene-n-  20:14.2 3 18/25 3.34 1.76 B B BuOH Toluene-n-  27:1 4.15 3 24/71 5.18 2.64 BB PrOH Xylene-EA   2:1 6 3 23/72 9.40 3.60 B B Heptane-EA   1:1.3 9.2 RT94 3.62 2.26 B + Z B Heptane-EA   1:1.3 9.2 RT 25 4.36 2.24 B BHexane-EA   1:1.2 8.8 RT 94 5.05 2.46 B B Hexane-EA   1:1.2 8.8 RT 252.72 2.32 B B Toluene- 5.7:1 4.7 3 22/72 5.56 2.88 B B acetone Legend:L/S—liquid/solid ratio (liquid = solvent + anti-solvent); ^(f)symbol RT→ 3 means that crystallization was started at room temperature then themixture was cooled to 3° C. to complete precipitation.

Example 7 Preparation of Form Delta

(A) This Example Illustrates Preparation of Nateglinide Form Delta byCrystallization from an Ethyl Acetate-Heptane Solvents System:

Preparation of Nateglinide Form δ

D-Phenylalanine (15.44 g) was added all at once to a 3.5% NaOH solution(370 ml, 3.5 equivalents), at 20° C., under stirring, 230 min⁻¹. A clearsolution was immediately formed. A neattrans-4-isopropylcyclohexylcarboxychloride (18.03 g) was added for 5minutes to the reaction solution. A solid was formed and the temperaturerose to 32° C. The mixture was stirred for 1 hour at 20° C., understirring. A 15% H₂SO₄ (56.1 g) was added all at once to the reactionmixture to adjust the pH to 1-2. The mixture was stirred for 1 h at 20°C. and the solid product was filtered off to afford cake—76 g of a wetproduct (moisture 65%). The product was dissolved in EA (200 ml), andthe aqueous phase was removed. The organic phase was concentrated at 50°C. under reduced pressure to afford 104 g of a turbid solution,containing 95 ml of EA. The solution was filtered and added for 30minutes to hot heptane (54° C., 250 ml). The initially formed solidcompletely dissolved after addition of ⅔ of the EA solution. The clearsolution was allowed to cool to 25°, seeded with B-form, and left forcrystallization overnight, under stirring at 215 revolutions min⁻¹. Thesolid was filtered off and washed with heptane (30 ml). The cake wasdried at 60° C./20 mbar to afford 6.84 g of the δ-form. Yield 33%.

Preparation of Nateglinide Form δ

D-Phenylalanine (20.00 g) was added all at once to a 3.5% NaOH solution(370.12 g, 2.7 equivalents), heated to 35° C., under stirring, 200min⁻¹. A clear solution was immediately formed. A neattrans-4-isopropylcyclohexylcarboxychloride (23.3 g) was added all atonce to the hot reaction mixture for 1 minute. A turbid solution wasformed and the temperature rose to 40° C. The mixture was stirred for 20minutes at 40-43° C. under stirring. An 85% solution of H₂SO₄ (11.94 g)was added all at once to the RM to adjust pH 1-2. The solid product wasextracted with EA (140 ml). The hot organic extract was washed with warmwater (100 ml), followed by brine (25 ml, 30.0 g) at 40° C., and driedwith anhydrous magnesium sulfate (3.05 g) over 1.5 hours. The organicsolution was filtered through a PTFE 0.45 μm filter, heated to 38° C.and to which was added hot heptane (40° C., 125 ml). The resulting clearsolution was gradually cooled for 45 minutes to 13° C. and seeded withNTG in B-form. The crystallization started. The mixture was then cooledfor 17 min to 5° C. and stirred for 16 h. The solid was filtered off andwashed with a cold (5° C.) mixture of heptane-EA mixture (5:1, total 180ml) to afford 36.49 g of a wet product (wetness 42.5%). The wet productwas dried at 60° C./13 mbar to afford 20.38 g of the product, Form δ,with a purity>99.8%. Yield 55%.

Preparation of Nateglinide Form δ

D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution(total 410.5 g, 2.99 equivalents), heated to 39° C., under stirring 150min⁻¹. A clear solution was immediately formed. A neattrans-4-isopropylcyclohexylcarboxychloride (24.73 g) was added all atonce to the hot reaction mixture. The mixture (clear solution) wasstirred for 25 minutes at 44-45° C., under stirring. Ethyl acetate (140ml), followed by an 85% solution of H₂SO₄ (14.08 g) were added all atonce to the reaction mixture to adjust the pH to 1-2. The hot organiclayer was separated, washed twice with water (100 ml) at 30° C., andfiltered through a PTFE 0.45 μm filter. The clear solution (141 g) washeated to 46° C. and to which was added hot heptane (46° C., 153 ml),under stirring at 150 min⁻¹. The clear solution was gradually cooled to28° C. and seeded with Form delta. The crystallization occurred at 24°C. The mixture was stirred for 30 minutes at 24° C., gradually cooled to5° C. and stirred overnight at 5° C. The solid was filtered off andwashed with a cold (5° C.) heptane-EA mixture (6:1, total 30 ml) toafford 49.1 g of a wet product in form delta (wetness 50%). The wetproduct was dried for 24 h at 23° C./20 mbar to afford 24.65 g of theproduct in a form delta with a purity>99.8%. Yield 65%.

(B) This Example Illustrates the Preparation of Form δ Crystallization

Crude nateglinide (50 grams) was dissolved in ethyl acetate (200 ml) andwater (2.5 ml) at 45° C. Hot heptane (260 ml) at 50° C. was added. Themixture was still fully dissolved. The mixture was cooled to 30° C. andseeded with nateglinide Form δ (0.1 grams). The mixture was stirred for30 minutes and then cooled to less than 10° C. in 2 hours. The mixturewas stirred at 5-10° C. overnight and then filtered with vacuum. The wetproduct was washed with ethyl acetate (100 ml) heptane mixture (ratio1:3 v/v). The wet product was dried in a vacuum oven at 50° C.overnight. Both the wet and dry samples were Form δ.

Starting material: Wet nateglinide (40% total wetness. 2 ml water, 10 mlethyl acetate, 21 ml of heptane). Wet crude nateglinide (83 grams) anddry nateglinide (50 grams) were dissolved in ethyl acetate (190 ml) at45° C. Hot heptane (239 ml) at 50° C. was added. The solution was cooledto 30° C. and a seeded with nateglinide (0.1 grams) Form δ. The mixturewas stirred for 30 minutes and then cooled to less than 10° C. in 2hours. The mixture was stirred at 5-10° C. overnight and then filteredwith vacuum. The wet product was washed with ethyl acetate-heptanemixture (100 ml) (ratio 1:3 v/v). The wet product was dried in a vacuumoven at 50° C. overnight. Both the wet and dry samples were Form δ.

(C) This Example Illustrates the Drying of Form δ by Fluidized Bed Dryer

Nateglinide Form delta (10 grams), with about 3% heptane (wt/wt), wasdried in a fluidized bed drier for 4 hours at 60° C. Residual heptanewas 1578 ppm af. Ethyl acetate is under detection limit. Polymorphicform of the dry product is delta.

According to these procedures, a series of experiments were carried outunder various heptane/ethyl ratios, liquid/solid ratios, temperature andseeding. The results are summarized in Table X:

TABLE X Data on crystallization of NTG in EA-Heptane solvents systemRatio Temperature Form Form Seed Anti-solvent v/v L/S, ml/g profileYield, % wet dry None Hexane 2.7:1 11 40(1) → 20(16) 58 Z B + Z NoneHeptane   4:1 16 40(1) → 20(16) 64 Z B None Heptane   5:1 11 40(1) →20(16) 74 H H None Heptane 4.7:1 11 40(1) → 20(16) 68 H H None Heptane7.5:  11 40(1) → 20(16) 48 B B None Heptane   5:1 8 40(1) → 20(16) 72 —H None Heptane   6:1 10 60(0.1) → 20(16) 76 B B None Heptane 7.1:1 1120(16) 78 H H B Heptane 5.1:1 14 5(1.5) → 5(1) 77 H H B Heptane 2.5:1 165(2) → 5(1) 74 H H B Heptane   1:1 7.5 16 → 5(16) 51 δ δ B Heptane   1:17 30(1) → 5(16) 58 δ δ B Heptane   1:1 7.6 13(1) → 5(16) 59 δ δ BHeptane   1:1 7.4 13(1) → 5(16) 55 δ δ B Heptane   2:1 9 30(0.5) → 5(1)76 H + U — 5(1) → 5(16) δ δ B Heptane 1.5:1 7.5 32(0.5) → 5 71 U — 5(1)U — 5(1) → 5(16) δ δ None Heptane   2:1 10 31(0.5) → 5(4.5) 67 δ δ NoneHeptane   1:1 — 9(0.5) → 5(1) — θ B 5(1) → 5(16) δ δ δ Heptane   1:1 7.89(0.5) → 5(16) 46 δ δ B Heptane 1.1:1 6.1 25(0.5) → 5(16) 63 δ δ δHeptane   1:1 7 19(0.5) → 5(16) 54 δ δ B Heptane   1:1 7.6 13(0.5) →5(16) 52 δ δ δ Heptane   1:1 6.1 30(0.5) → 5(16) 55 δ δ Temperatureprofile: crystallization temperature (h) → final temperature (h); L,t—amount of L, trans-isomer.

Example 8 This Example Illustrates Preparation of Forms of Nateglinideby Precipitation without Going to Solution after Combining

Preparation of Nateglinide Form U

D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution(369.73 g, 2.7 equivalents), at 20° C., under stirring, 200 revolutionsmin⁻¹. A clear solution was immediately formed. A neattrans-4-isopropylcyclohexylcarboxychloride (23.9 g) was added all atonce to the hot reaction solution for 1 minute. A solid was formed andthe temperature rose to 32° C. The mixture was stirred for 40 minutes at20° C., under stirring. An 85% solution of H₂SO₄ (11.55 g) was added allat once to the reaction mixture to adjust the pH to 1-2. The solidproduct was extracted with EA (150 ml) at 55° C. for 55 minutes. The hotorganic extract was washed with warm water (100 ml), followed by brine(40° C., 50 ml), dried with anhydrous sodium sulfate (10 g) over 1.5 h,and filtered. The excess of EA was removed under reduced pressure toafford 86 g of the solution, containing ˜54 g (60 ml) of EA. The EAsolution was finally filtered through a PTFE 0.45 μm filter into a cleandropping funnel heated to 35° C. Heptane (320 ml) was placed into thereactor, cooled to 5° C., and seeded with B-form. The clear hotEA-solution was added for 5 minutes to the cold heptane, under stirring.Precipitation immediately happened to afford a solid. The mixture wasstirred for 2.5 hours at 5° C. The solid was filtered off and washedwith a cold (5° C.) mixture of heptane-EA mixture (4.5:1, total ˜120 ml)to afford 63.62 g of a wet product (wetness 54%). The cake (62.4 g) wasdried at 60° C./10 mbar to afford 28.6 g of the product, containing˜0.6% of L,trans-isomer (other impurities<0.1%) in the U-form. Yield77%.

TABLE XI Data on crystallization of NTG during the crystallizationprocess (precipitation without going into solution after combining)Anti- Ratio L/S, T_(EA), T_(AS)(time), Form Form Seed solvent v/v ml/g °C. ° C.(h) Yield, % L, t, % wet dry B Heptane 3.7:1 17 25 55(25) 33 0.05δ δ None Heptane 5.4:1 12 40 5(2.5) 77 0.7 U U None Heptane 0.77:1  9.745 45 → 25(1) 71 0.01 B + U 25(1) → 2 U U 25(22) None Heptane 0.8:1 9.745 45 → 25(21) 72 0.03 σ σ T_(EA)—temperature of the EA solution;T_(AS)(time)—temperature of anti-solvent (exposure time) → finaltemperature (exposure time); L, t—amount of L, trans-isomer.

Example 9 Heating of Nateglinide Form U

Sample of nateglinide form U (˜1 g) was introduced into a 6-gram vialand heated over 8.5 h in a 100° C. oil bath. The vial were extractedfrom the bath. The resulted sample showed Form U by XRPD.

Sample of nateglinide form U (˜0.5 g) was heated to 120° C. for 1 h inan atmospheric pressure. The resulted sample showed Form U by XRPD.

Example 10 Heating of Nateglinide Form δ

Sample of nateglinide form δ (˜0.5 g) was heated to 120° C. for 1 h inan atmospheric pressure. The resulted sample showed Form B by XRPD.

Example 11 Preparation of Form Omega

Nateglinide Form delta (5 grams) was dissolved in isopropanol (15 ml) atroom temperature. The solution was cooled to ˜0° C. Water (6 ml) wasadded. A white solid precipitated suddenly. The solid was heated to 35°C., resulting in complete dissolution. The solution was cooled to ˜7° C.and the product precipitated. The product was filtered with vacuum. XRPDconfirmed the presence of Form omega.

Example 12 Drying of a Wet Sample of Form Omega

The product of example 11 was dried at 50° C. in a vacuum ovenovernight, and analyzed by XRD. A mixture of Form omega and Form Z wasobtained.

Example 13 This Example Illustrates the Preparation of Form U byTriturating Form δ in Ethyl-Acetate

Nateglinide Form δ (5 grams) was triturated in ethyl acetate (10 ml) at25° C. for 2 hours. The wet material was filtered with vacuum and washedwith ethyl acetate (10 ml). The wet product was dried at 50° C. in avacuum oven overnight. The wet and dry products were Form U.

Example 14 This Example Illustrates the Preparation of Form B byTriturating Form δ in Ethyl-Acetate

Nateglinide Form δ (5 grams) was triturated in ethyl acetate (10 ml) at50° C. for 1 hour. The mixture was cooled to 20° C. and triturated for 1hour. The wet material was filtered with vacuum and washed with ethylacetate (10 ml). The wet product was dried at 50° C. in a vacuum ovenovernight. The wet and dry products were obtained as Form B.

Example 15 Process for the Preparation of Nateglinide Form B

Nateglinide Form B may also be obtained by precipitation of nateglinideForm G, from isopropanol followed by conversion of Form G to Form B. Inthis embodiment, a form of nateglinide, such as nateglinide Form δ(about 3% LOD) is dissolved in a mixture of IPA/H₂O at a preferredtemperature range of about 40 to about 50° C. Preferably, the IPAconcentration in the solvent mixture is in the range of about 50% toabout 70% (v/v), and the volume of the solvent mixture is about 5 toabout 20 volumes/unit weight of nateglinide.

The solution obtained after dissolution is preferably cooled to atemperature of about 30° C. for seeding with crystals of Form B. Theseeded solution is preferably stirred at the seeding temperature forabout 30 minutes to about 3 hours. The solution is preferably thencooled to about 0° C. plus/minus 5° C. for at preferably least about 5hours, and preferably stirred at 5° C. for at least about 30 minutes.The precipitated nateglinide crystals may be recovered and dried underreduced pressure at a preferred temperature of about 70 to about 90° C.to obtain nateglinide Form B.

In this embodiment, before crystallization, the starting material mayoptionally be dissolved in IPA or in a IPA/H₂O mixture (in the samesolvent ratio as the crystallization mixture), followed by evaporationunder reduced pressure. After the evaporation, IPA/H₂O mixture is fedinto the reactor to obtain a solution. Nateglinide Form B is obtainedafter the evaporation.

The use of IPA allows for the elimination of methyl esters as impuritiesin the final product as illustrated in FIG. 64.

Example 15 (A)

Nateglinide (40 grams) was dissolved in IPA (240 ml) at 25° C. Thesolution was filtered to remove insoluble materials. The clear solutionwas heated to 50° C. and stirred for 5 hours. After stirring, thesolvent was evaporated under reduced pressure. The residue was tested byXRD and found to be B type.

Example 15 (B)

Nateglinide (30 grams) was dissolved in IPA (150 ml) in a reactor. Thesolvent was evaporated under reduced pressure at a jacket temperatureTj=50° C. A solution was obtained by feeding the reactor with IPA (150ml) and water (150 ml) were fed at Tj=50° C. The clear solutionobtained, was cooled to TR=29.4° C., and seeded by B type crystals. Theseeded solution was stirred at TR=29.4° C. for additional 3 hours, andafterwards cooled to TR=0° C. for 10 hours. At 0° C., the resultingslurry was stirred for additional 5 hours (over-night). The crystalswere isolated and dried under reduced pressure at 90° C. The wetcrystals were tested by XRD and found to be G type. The dried crystalswere tested by XRD and found to be B type.

Example 15 (C)

Nateglinide (20 grams) was dissolved in IPA (200 ml) in a round bottomflask and the solvent was evaporated under reduced pressure at atemperature of 50° C. IPA (200 ml) and water (200 ml) were fed into theround bottom flask to obtain a clear solution. The solution wastransferred to a reactor and cooled to a temperature of TR=28° C. At 28°C., the solution was seeded with type B crystals.

The seeded solution was stirred at 28° C. for an additional 2 hours, andafterwards cooled to 5° C. for 10 hours. At 5° C., the solution wasstirred for an additional 4 hours (overnight). The product was isolatedand dried under reduced pressure at 90° C. The wet crystals were testedby XRD and found to be G type. The dried crystals were tested by XRD andfound to be B type.

Example 16 Process for the Preparation of Nateglinide Form B byTrituration in Water

Nateglinide Form δ was triturated in 5 volumes water at about 25° C. forabout 7 hours. The crystals were isolated and dried under reducedpressure at 90° C.

Example (A) Trituration of Wet Starting Material

50 gr Nateglinide form δ wet (about 37% LOD) was triturated in 250 mlwater at 25° C. After 4 hrs trituration, the slurry was sampled anddried under reduced pressure at 90° C. The wet crystals were tested byXRD and found to be δ type. The dry crystals were tested by XRD andfound to be B type. After 7 hours of trituration, the product wasisolated and dried under reduced pressure at 90° C. The wet crystalswere tested by XRD and found to be δ type. The dry crystals were testedby XRD and found to be B type.

Example (B) Trituration of Dry Starting Material

50 gr Nateglinide form δ dry was triturated in 250 ml water at 25° C.After 4.5 hrs trituration, the slurry was sampled and dried underreduced pressure at 90° C. The wet crystals were tested by XRD and foundto be Z type. The dry crystals were tested by XRD and found to be Btype. After 7.5 hours of trituration, the product was isolated and driedunder reduced pressure at 90° C. The wet crystals were tested by XRD andfound to be E type. The dry crystals were tested by XRD and found to beB type.

Example 17 Preparation of Nateglinide form U Example (A) Crystallizationfrom Acetone

Nateglinide (50 grams) Form δ was dissolved in acetone (175 ml) at 42°C. The clear solution was cooled to 10° C. for seeding. After seedingwith type B crystals, the seeded solution was stirred for an additional3 hours at a temperature of 10° C. and cooled to −10° C. for 10 hours,and stirred at −10° C. over night. The crystals were isolated and driedat 90° C. The wet crystals were tested by XRD and found to be U type.The dry crystals were tested and found to be U type.

Example (B) Crystallization from Ethyl Acetate

Nateglinide (20 grams) were dissolved in ethyl acetate (560 ml) at 40°C. The solution was filtered to remove insoluble matter. The clearsolution was evaporated under reduced pressure, and Ethyl Acetate (460ml) was evaporated (the solvent volume in the reactor was 5 volumes/unitweight Nateglinide). The solution was cooled to 20° C. and seeded withtype B crystals. The seeded solution was stirred at 20° C. for anadditional 30 minutes, cooled to 0° C. for 1.5 hours, and stirred at 0°C. for an additional 30 minutes. The crystals were isolated and driedunder reduced pressure at 30° C., 50° C., 90° C. The wet crystals weretested by XRD and found to be U type. The dry crystals were tested byXRD and found to be U type.

Example 18 Removal of Residual Solvent from Form Delta

Nateglinide (40 grams) Form delta (1.5% heptane) was dried in a stirredreactor (7-10 rpm) under 60 mmHg vacuum and at 60° C. After 6 hours ofdrying, the residual solvent of the material was 613 ppm of heptane. Thepolymorph of the dried material remained delta form, as the startingmaterial.

Example 19 Preparation of Nateglinide Form B from Ethyl Acetate

Nateglinide form δ is dissolved in ethyl acetate at 25° C. The solventis evaporated under reduced pressure, until turbidity appears. Theturbid solution is cooled to 0° C. plus/minus 5° C. for 1 hour andstirred for 1 hour. The product was isolated and dried under reducedpressure at 50° C.

Example (A)

Nateglinide (12 grams) Form δ was dissolved in 165 ml of ethyl acetateat 25° C. The solvent was evaporated under reduced pressure at 25° C.,until turbidity appeared. At the end of evaporation, the volume in thereactor was 90-95 ml. The mixture was cooled from 25° C. to 5° C. for 1hour and stirred at 5° C. for 1 hour. The product was isolated and driedunder reduced pressure at 50° C. Both the wet and the dry crystals weretested by XRD and DSC and found to be B type.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art mayappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to, limit its scope in any way. The examples do not includedetailed descriptions of conventional methods. Such methods are wellknown to those of ordinary skill in the art and are described innumerous publications. Polymorphism in Pharmaceutical Solids, Drugs andthe Pharmaceutical Sciences, Volume 95 may be used as a guidance. Allreferences mentioned herein are incorporated in their entirety.

1. A crystalline form of nateglinide (Form ε) characterized by dataselected from the group consisting of: an XRPD pattern with peaks at4.2, 13.0, 13.6, 14.3, 16.2, 16.7 and 19.6±0.2 degrees 2θ; and a DSCthermogram with endotherms at about 64, 108 and 129° C.
 2. Thecrystalline form of claim 1, wherein the crystalline form ischaracterized with peaks at 4.2, 13.0, 13.6, 14.3, 16.2, 16.7 and19.6±0.2 degrees 2θ.
 3. The crystalline form of claim 2, wherein thecrystalline form has an XRPD pattern as depicted in FIG.
 25. 4. Aprocess for preparing the crystalline form of claim 1 comprising thesteps of: a) preparing a solution of nateglinide in a solvent selectedfrom the group consisting of acetone, acetonitrile and nitromethane; b)crystallizing the crystalline form from the solution; and c) recoveringthe crystalline form.
 5. The process of claim 4, wherein the solvent isacetone.
 6. The process of claim 4, wherein the solvent is acetonitrile.7. The process of claim 4, wherein the solvent is nitromethane.
 8. Aprocess for preparing the crystalline form of claim 1 comprising thesteps of: a) triturating a crystalline form of nateglinide innitromethane to obtain the crystalline form of claim 1, with the provisothat the crystalline form triturated is not Form U; and b) recoveringthe crystalline form of claim
 1. 9. The process of claim 8, wherein thecrystalline form triturated is Form H.
 10. Crystalline form epsilon ofnateglinide of claim 1, wherein the crystalline form is a solvate of asolvent selected from the group consisting of acetone, acetonitrile andnitromethane.